The studies focus on the immune mechanisms responsible for the production of renal injury in humans. The immune forms of renal injury account for more than half of the cases of renal failure than lead to end-stage renal disease management using dialysis and transplantation. Our long-term goal is to understand these mechanisms so that we can manipulate them to therapeutic advantage. The major mechanisms center on the glomerular accumulation of antibodies by a number of means in turn activating mediator systems to cause injury. Anti-glomerular basement membrane (GBM) antibodies typify these mechanisms. Using biochemical and molecular techniques, we will continue to define the nature of the antigens reactive with anti-GBM antibodies with the goal of defining the peptide nature of the reactive epitope(s). This information should standardize diagnosis, define individual differences, and provide advances in therapy by selective removal of antibody or interference with antibody production or reactivity. Of the potential mediators we will explore the poorly understood contributions of coagulation and monocyte/endothelial procoagulant activity using human renal biopsies through a combination of monoclonal antibody studies and in situ hybridization techniques with probes specific for tissue factor and inducing molecules such as interleukin-1 (I1-1), and tumor necrosis factor-alpha. Other studies of activation elements produced by immune cells, as well as the contributions of products of viral agents to glomerular injury, can be studied with similar techniques as time permits. The direct glomerular effects of biologically active coagulation protein fragments will be evaluated in the isolated perfused kidney to examine their role independent of the complex cellular and humoral mediation pathways normally present in the intact vascular compartment. A number of other active mediator molecules are available for this type of direct evaluation. We have shown that antibodies can cause selective glomerular cell damage. We will explore the mesangial proliferative responses that follow acute injury in our model of anti-mesangial cell antibody injury. The mesangial cell is central in many types of immune glomerular injury via its role in handling immune related materials and its release of endogenous phlogenic materials including I1-1 that may contribute to destruction of the glomerulus.